Recanalization of Chronically Occluded Aorto-Coronary Saphenous Vein Bypass Grafts With Long-Term, Low Dose Direct Infusion of Urokinase Trial - ROBUST

Description:

ROBUST was a multicenter study designed to investigate the short-term efficacy and safety of a prolonged, low-dose, intragraft infusion of urokinase for the recanalization of chronically occluded saphenous vein bypass grafts.

Hypothesis:

A directed and prolonged infusion of urokinase would result in the recanalization of totally occluded saphenous vein bypass grafts, with sustained epicardial patency at six months.

Study Design

Study Design:

Patients Enrolled: 107
Mean Follow Up: Six months
Mean Patient Age: Mean 61 years
Female: 21

Patient Populations:

Patients <75 years old with prior aortocoronary venous bypass grafts and all of the following: Canadian Cardiovascular Society class III-IV angina unresponsive to medical therapy; a totally occluded, single, end-to-side nonsequential bypass graft considered to be the cause of ischemia; and native vessel not amenable to balloon angioplasty

Exclusions:

Acute MI within 24 hours; contraindication to thrombolytic, aspirin, or warfarin; flush (ostial) occlusion of the vein graft; inability to advance a guide wire at least 1 cm into the graft; serum creatinine >2 mg/dl; or history of paroxysmal or chronic atrial fibrillation

Primary Endpoints:

Initial vessel patency

Secondary Endpoints:

Six-month vessel patency; adverse events

Drug/Procedures Used:

Urokinase infusion (50,000 U/h both proximally and distally) was administered into the occluded bypass graft via a 0.035 inch infusion wire, with balloon angioplasty performed after thrombus was resolved or no further improvement was seen. Urokinase infusion was continued for at least 24 hours and could be increased to 250,000 or 360,000 U/h if no recanalization was observed on subsequent angiography.

Concomitant Medications:

Anticoagulation with heparin. Patients were discharged on aspirin and warfarin.

Principal Findings:

A total of 107 patients were administered the urokinase infusion, with the majority of patients enrolled within three months of the likely time of graft occlusion manifested by an acute change in symptoms. The initial recanalization rate was 69% (95% confidence interval [CI] 59-78%).

Among the 72 patients who actually met entry/exclusion criteria and were administered the study medication according to protocol (33% of patients were classified as protocol violations), success rates were 78% (95% CI 66-87%). Immediate success did not correlate with the age of the graft or the likely duration of occlusion. The mean urokinase infusion dosage in patients treated successfully was 3.63 million U, with a mean infusion time of 25.7 hours.

The most frequent complication was cardiac enzyme elevation (17%), with death in 6.5% of patients (none with successful recanalization) and Q-wave myocardial infarction (MI) in 5%. Among 40 of the 74 patients with successful recanalization who underwent follow-up angiography, 40% of treated grafts were patent on follow-up, with higher rates in patients who achieved TIMI grade 3 flow after the initial urokinase infusion (but before balloon angioplasty). Angina was less frequent among patients with successful recanalization (22% vs. 71%, p<0.001).

Interpretation:

In this multicenter trial of a prolonged duration of directed urokinase infusion for totally occluded aortocoronary saphenous vein bypass grafts, treatment with urokinase was associated with an almost 70% early patency rate, which decreased to 40% at six months.

There are several notable caveats to this data. The patient population was highly selected, and protocol violations occurred in 33% of enrolled patients. Patients in whom the protocol violations occurred had lower initial patency rates (51%) and more complications (six of the seven deaths occurred in these patients). Cardiac enzyme elevation occurred in 17% of patients overall (and 16% of successfully treated patients), suggesting that distal embolization remains a problem even among successfully treated patients.

References:

Hartmann JR, McKeever LS, O'Neill WW, et al. Recanalization of Chronically Occluded Aortocoronary Saphenous Vein Bypass Grafts With Long-Term, Low Dose Direct Infusion of Urokinase (ROBUST): a serial trial. J Am Coll Cardiol 1996;27:60-6.

Clinical Topics: Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Lipid Metabolism, Novel Agents

Keywords: Myocardial Infarction, Follow-Up Studies, Urokinase-Type Plasminogen Activator, Thrombosis, Saphenous Vein, Coronary Disease, Fibrinolytic Agents, Confidence Intervals, Angioplasty, Balloon, Coronary


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